Search

Cardiovascular disease is a common comorbidity in patients with cancer, and the main leading cause of noncancer-related deaths in cancer survivors. Considering that current antitumor drugs usually induce cardiovascular injury, the quest for developing new antitumor drugs, especially those with cardiovascular protection, is crucial for improving cancer prognosis. MK2206 is a phase II clinical anticancer drug and the role of this drug in cardiovascular disease is still unclear. Here, we revealed that MK2206 significantly reduced vascular inflammation, atherosclerotic lesions, and inhibited proliferation of vascular smooth muscle cell in ApoE(−/−) mice in vivo. We demonstrated that MK2206 reduced lipid accumulation by promoting cholesterol efflux but did not affect lipid uptake and decreased inflammatory response by modulating inflammation-related mRNA stability in macrophages. In addition, we revealed that MK2206 suppressed migration, proliferation, and inflammation in vascular smooth muscle cells. Moreover, MK2206 inhibited proliferation and inflammation of endothelial cells. The present results suggest that MK2206, as a promising drug in clinical antitumor therapy, exhibits anti-inflammatory and antiatherosclerotic potential. This report provides a novel strategy for the prevention of cardiovascular comorbidities in cancer survivors.

Background: Immunoglobulin E (IgE) belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor (FcεR1) in pathological cardiac remodeling and heart failure are unknown. Methods: Serum IgE levels and cardiac FcεR1 expression were assessed in diseased hearts from human and mouse. The role of FcεR1 signaling in pathological cardiac remodeling was explored in vivo by FcεR1 genetic depletion, anti-IgE antibodies, and bone marrow transplantation. The roles of the IgE-FcεR1 pathway were further evaluated in vitro in primary cultured rat cardiomyocytes and cardiac fibroblasts (CFs). RNA sequencing and bioinformatic analyses were used to identify biochemical changes and signaling pathways that are regulated by IgE/FcεR1. Results: Serum IgE levels were significantly elevated in patients with heart failure as well as in 2 mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin II infusion. Interestingly, FcεR1 expression levels were also significantly upregulated in failing hearts from human and mouse. Blockade of the IgE-FcεR1 pathway by FcεR1 knockout alleviated transverse aortic constriction– or angiotensin II–induced pathological cardiac remodeling or dysfunction. Anti-IgE antibodies (including the clinical drug omalizumab) also significantly alleviated angiotensin II–induced cardiac remodeling. Bone marrow transplantation experiments indicated that IgE-induced cardiac remodeling was mediated through non–bone marrow–derived cells. FcεR1 was found to be expressed in both cardiomyocytes and CFs. In cultured rat cardiomyocytes, IgE-induced cardiomyocyte hypertrophy and hypertrophic marker expression were abolished by depleting FcεR1. In cultured rat CFs, IgE-induced CF activation and matrix protein production were also blocked by FcεR1 deficiency. RNA sequencing and signaling pathway analyses revealed that transforming growth factor-β may be a critical mediator, and blocking transforming growth factor-β indeed alleviated IgE-induced cardiomyocyte hypertrophy and cardiac fibroblast activation in vitro. Conclusions: Our findings suggest that IgE induction plays a causative role in pathological cardiac remodeling, at least partially via the activation of IgE-FcεR1 signaling in cardiomyocytes and CFs. Therapeutic strategies targeting the IgE-FcεR1 axis may be effective for managing IgE-mediated cardiac remodeling.

Rationale: Hypertension is a common chronic disease, and its prevalence is increasing. Immunoglobulins play crucial roles in adaptive immune response and have been implicated in the pathogenesis of hypertension. However, which immunoglobulins and receptors as well as underlying mechanisms participating in hypertension remains unknown. We found that IgG is significantly increased in hypertensive patients, suggesting a potential association between IgG signaling and hypertension. Objective: This study is aimed to investigate the role and underlying mechanism of IgG and its receptor in hypertension. Methods and Results: We showed that serum IgG and the expression of IgG receptor FcγR (Fcγ receptor) IIB in vessel were significantly increased in hypertensive mice. Blockade of FcγRIIB function significantly reduced Ang II (angiotensin II)–induced vascular remodeling and hypertension in mice with genetic ablation of FcγRIIB or with systemic anti-FcγRIIB antibody treatment in mice. The studies with bone marrow transplantation approach or smooth muscle cell (SMC)–specific FcγRIIB ablation revealed that the role of FcγRIIB in vascular remodeling and hypertension is largely dependent on SMCs but not bone marrow–derived cells. Interestingly, we found that FcγRIIB expressed in SMCs is important in SMC-dependent vascular contraction ex vivo, as well as Ang II–induced SMC hypertrophy and matrix protein expression in vitro. Mechanistic studies further revealed that IgG stimulates FcγRIIB association with AT1R (Ang II type 1 receptor) in SMCs and inhibits AT1R internalization, thus increasing the cell membrane AT1R level. Furthermore, FcγRIIB-mediated regulation of AT1R internalization is critical for Ang II–induced SMC ERK (extracellular signal-regulated kinase) 1/2 activation and hypertrophy, as well as for Ang II–induced arterial contraction. Conclusions: Taken together, our findings indicate that IgG/FcγRIIB contributes to vascular remodeling and hypertension, at least partially through suppressing AT1R internalization in SMCs. Our findings also suggest that FcγRIIB may represent an innovative therapeutic target for hypertension, especially for patients with autoimmune diseases.

Pathological cardiac remodeling, characterized by excessive deposition of extracellular matrix proteins and cardiac hypertrophy, leads to the development of heart failure. Meprin α (Mep1a), a zinc metalloprotease, previously reported to participate in the regulation of inflammatory response and fibrosis, may also contribute to cardiac remodeling, although whether and how it participates in this process remains unknown. Here, in this work, we investigated the role of Mep1a in pathological cardiac remodeling, as well as the effects of the Mep1a inhibitor actinonin on cardiac remodeling-associated phenotypes. We found that Mep1a deficiency or chemical inhibition both significantly alleviated TAC- and Ang II-induced cardiac remodeling and dysfunction. Mep1a deletion and blocking both attenuated TAC- and Ang II-induced heart enlargement and increases in the thickness of the left ventricle anterior and posterior walls, and reduced expression of pro-hypertrophic markers, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and myosin heavy chain beta (β-MHC). In addition, Mep1a deletion and blocking significantly inhibited TAC- and Ang II-induced cardiac fibroblast activation and production of extracellular matrix (ECM). Moreover, in Mep1a-/- mice and treatment with actinonin significantly reduced Ang II-induced infiltration of macrophages and proinflammatory cytokines. Notably, we found that in vitro, Mep1a is expressed in cardiac myocytes and fibroblasts and that Mep1a deletion or chemical inhibition both markedly suppressed Ang II-induced hypertrophy of rat or mouse cardiac myocytes and activation of rat or mouse cardiac fibroblasts. In addition, blocking Mep1a in macrophages reduced Ang II-induced expression of interleukin (IL)-6 and IL-1β, strongly suggesting that Mep1a participates in cardiac remodeling processes through regulation of inflammatory cytokine expression. Mechanism studies revealed that Mep1a mediated ERK1/2 activation in cardiac myocytes, fibroblasts and macrophages and contributed to cardiac remodeling. In light of our findings that blocking Mep1a can ameliorate cardiac remodeling via inhibition of cardiac hypertrophy, fibrosis, and inflammation, Mep1a may therefore serve as a strong potential candidate for therapeutic targeting to prevent cardiac remodeling.

BACKGROUND Recently, mutations in several genes have been described to be associated with sporadic ASD, but some genetic variants remain to be identified. The aim of this study was to use whole-exome sequencing (WES) combined with bioinformatics analysis to identify novel genetic variants in cases of sporadic congenital ASD, followed by validation by Sanger sequencing. MATERIAL AND METHODS Five Han patients with secundum ASD were recruited, and their tissue samples were analyzed by WES, followed by verification by Sanger sequencing of tissue and blood samples. Further evaluation using blood samples included 452 additional patients with sporadic secundum ASD (212 male and 240 female patients) and 519 healthy subjects (252 male and 267 female subjects) for further verification by a multiplexed MassARRAY system. Bioinformatic analyses were performed to identify novel genetic variants associated with sporadic ASD. RESULTS From five patients with sporadic ASD, a total of 181,762 genomic variants in 33 exon loci, validated by Sanger sequencing, were selected and underwent MassARRAY analysis in 452 patients with ASD and 519 healthy subjects. Three loci with high mutation frequencies, the 138665410 FOXL2 gene variant, the 23862952 MYH6 gene variant, and the 71098693 HYDIN gene variant were found to be significantly associated with sporadic ASD (P

Objective By establishing the indirect contact co-culture system, we studied the in vitro condition for MAPCs differentiating into epidermal cells and the transformation of MAPCs into epidermal cell phenotype. Methods Cell culture insert membrane was used for substitute basal membrane and MAPCs, fibroblast cells (FCs) and mixture of MAPCs and epidermal cells and FCs were separately implanted into 2 sides of it. PKH26 was used to label cloned MAPCs; type IV collagen rapid adhering method was used to isolate and culture the skin epidermal cells from 1-day-old SD rat. Results Part of the MAPCs transformed into cells expressing keratin in the presence of peripheral epithelia and FCs. Type IV collagen rapid adhering method successfully selected rats' epidermal stem cells. The mixture of the 2 kinds of cells or indirect culture might promote the differentiation through mesenchymal factors secreted by dermis FC. Conclusion We were the first to have established the in vitro model of MAPCs differentiation into epidermal cells, in which MAPCs were transformed into epithelium-like cells.

The telomerse activity in condyloma acuminatum (CA) tissue with human papillomavirus (HPV) types of 6/11 and 16/18 was detected to investigate the function of telomerase in the occurrence, development and carcinogenesis of genital CA. Forty-two biopsies from patients with gennital CA and 30 control tissue samples were tested for telomerase activity, HPV presence and types. The telomerase activity was determined by modified telomerase repeat amplification protocol (TRAP) assay and HPV typing by polymerase chain reaction (PCR) with typing-specific primers. Results showed that HPV-DNA was negative and the expression rate of telomerase was 16.7% in all normal skin samples. All CA samples were positive for HPV (6/11 type was found in 32 cases, 16/18 in 3 and mixed type in 7). Telomerase activity was detectable in all CA patients. The telomerase activity in CA of 16/18 type was apparently higher than in CA of 6/11 type. It was concluded that the hypperplasia in CA might be increased as a result of HPV infection, suggesting that the activation of telomerase by HPV, especially by 16/18 type may play a role in the etiology and carcinogenesis of genital CA.

Background: Recent evidence has suggested that p63 plays a particular role in maintaining the population of epidermal stem cells (ESCs), but the expression pattern of p63 during normal rat epidermis development is still unknown. We investigated the expression of p63 during development and differentiation of rat epidermis and identified whether p63 is a specific marker of rat ESCs cultured in vitro. Methods: Skin biopsies were obtained from embryonic day (E) 12 rat embryo, newborn, and 4-week-old rats. Immunohistochemistry was used to monitor the expression profile of p63. ESCs were isolated from newborn rat epidermis by rapid adhesion to IV collagen and examined by immunofluorescence staining to detect p63 and k14 expression. Results: P63 expression was first observed at E12 when the epidermis was only a simple-layer surface ectoderm. P63 continued to be expressed as the epidermis matured but restricted to the basal layer. In adult trunk epidermis, p63 was expressed in both the hair follicle and the sebaceous glands. Immunofluorescence staining for ESCs was double positive for p63 and k14. Conclusions: These expression data suggest a role of p63 in the development of rat epidermis. P63 transcription factor may be a specific marker of keratinocyte progenitor cells.

To overcome some of the problems inherent in conventional hearing aids such as low gain at high frequencies due to acoustic feedback, discomfort in occlusion of the external ear canal and so on, implantable middle ear hearing devices (IMEHDs) have been developed over the past two decades. For such kinds of IMEHDs, this paper presents the design of a floating mass piezoelectric actuator using a PMN-30%PT stack as a new type of vibrator. The proposed piezoelectric actuator consists of only three components of a piezoelectric stack, a metal case and a clamp. For the purpose of aiding the design of this actuator, a coupling biomechanics model of human middle ear and the piezoelectric actuator was constructed. This model was built based on a complete set of computerized tomography section images of a healthy volunteer’s left ear by reverse engineering technology. The validity of this model was confirmed by comparing the motion of the tympanic membrane and stapes footplate obtained by this model with published experimental measurements on human temporal bones. It is shown that the designed actuator can be implanted on the incus long process by a simple surgical operation, and the stapes footplate displacement by its excitation at 10.5 V root-mean-square(RMS) voltage was equivalent to that from acoustic stimulation at 100 dB sound pressure level(SPL), which is adequate stimulation to the ossicular chain. The corresponding power consumption is 0.04 mW per volt of excitation at 1 kHz, which is low enough for the transducer to be used in an implantable middle ear device.